Since the anti-angiogenic agent avastin (bevacizumab) has been shown to confer a survival benefit in a subset of patients with previously untreated advanced NSCLC (see prior post), we have been struggling with questions of whether the restricted eligibility requirements in the pivotal initial avastin trial were necessary. Specifically, the trial, called ECOG 4599 (abstract here) excluded patients with squamous NSCLC, known brain metastases, on full dose anticoagulation/blood thinners (not low, prophylactic doses that are occasionally used to try to prevent patients from developing blood clots), with a history of clots or bleeding problems, or with a history of coughing up blood. While the trial was positive, these exclusion requirements have left only a minority of real world patients in the real world eligible for avastin -- most experts estimating perhaps 30-50% of advanced NSCLC patients. Since then, the question has remained whether these exclusions are really necessary or are actually overly conservative. For example, avastin had already been approved for patients with advanced colon cancer, in whom there is no restriction on blood thinners or presumed need to check for brain metastases in that population. These restrictive factors have been evaluated over the last few years to try to establish whether it may be feasible to treat patients with these potentially "soft" exclusion factors with avastin.

Patients enrolling on trials to receive avastin have historically been excluded if they had a history of brain metastases, even treated with radiation or surgery, based on a single case in a phase I trial early in avastin's development, in which a patient with liver cancer had an unsuspected brain metastasis and developed a fatal bleeding event in the brain (abstract here). Since then, avastin has been studied with chemo in some small trials of patients with primary brain tumors (cancers that originate in the brain, as opposed to the more commen reason for tumors in the brain, which is from spread to the brain from another source, most commonly lung cancer). In these trials, a few dozen patients with brain cancers have received avastin, and there has been a single reported bleed in the central nervous system (CNS, basically just another way of saying "brain") thus far (abstracts here and here).

Since avastin was approved, there has been a change in practice for patients with advanced NSCLC. Before avastin was approved, many oncologists did not routinely perform head MRI scans looking for brain metastases if a patient was already known to have advanced NSCLC and did not have any neurologic symptoms. The idea was that there was little reason to look for brain metastases if some patients would never have symptoms from them, and if it didn't need to change management. In fact, there is some evidence that patients can have shrinkage of brain metastases from chemotherapy that is in the same range as that seen outside of the brain (post here), leaving even less incentive to jump in to treat something that could be treated along with the cancer in the chest and elsewhere. But with avastin approved only for lung cancer patients with no evidence of brain metastases, we now go looking for brain metastases routinely in patients who are otherwise appropriate candidates for avastin. And now that we do head MRIs looking for them, we find them more commonly than we used to suspect; I and other lung cancer experts have estimated that somewhere in the range of 10-20% of patients will now be found to have brain metastases when you look hard for them. So there are many patients who are technically ineligible for avastin based on prior brain metastases. On the other hand, I've seen many patients in second opinions who have received avastin despite their having treated brain mets; some very good oncologists just provide a careful discussion of risk and benefit balance with avastin and treat patients with brain metastases despite the potentially increased risk of bleeding, especially since we really don't know whether we're just being paranoid. In fact, though, there were three patients on the avastin arm of the ECOG 4599 trial who developed bleeding in the brain, at least one of whom with new development of brain metastases that hadn't been seen on initial presentation (Sandler, personal communication).

In the last few years, Genentech, the maker of avastin, has run a couple of trials that have tried to assess the actual risk. One is called PASSPORT, which is a phase II study that since March, 2006 has been enrolling patients with treated brain metastases but not patients with nonsquamous NSCLC, and no metastases in the brainstem (the lower part of the brain that controls many automatic functions of the body) or in the meninges (lining around the brain and spinal cord). Treatment with chemo and avastin must start at least 4 weeks after completing brain radiation (this delay may lead many potentially eligible candidates to not enroll, since they may be eager to start chemo-based treatment sooner than that). This trial is ongoing.

Another study that includes patients with brain metastases is the much larger ATLAS trial, testing whether patients benefit from having tarceva added to maintenance avastin in patients without progression after four cycles of chemo and avastin:

(Click on image to enlarge)

Patients can't be on steroids or have neurologic symptoms related to their brain metastases.

Some preliminary results of 42 patients with brain mets who have been enrolled on the PASSPORT and ATLAS trials has recently been presented (abstract here). With a median of 3 doses of avastin given to these patients, there was just a single episode of nonfatal bleeding in the brain (in a patient who had already come off of treatment for progression), and two patients on PASSPORT developed new seizures, unclear if related to the avastin.

Finally, in addition to these trials run by the company, Dr. Heather Wakelee of Stanford is running her own phase II trial of alimta with avastin as a second line therapy for patients with treated brain metastases. We don't have any results from that study yet. Further information on this trial is available here.

While we don't have clear answers yet about the safety of giving avastin to patients with treated brain metastases, these trials will add to the ad hoc clinical experience of the physicians who are doing this already. I have been reluctant to treat patients with brain mets off protocol with avastin, but if additional publications support the general safety of avastin in trials like those described above, I think we'll see a growing comfort level with broadening the use of avastin to include another 10-20% of patients now disqualified or at least discouraged from receiving avastin.

I'll cover some more of these points of contention with avastin in upcoming posts.